TRIM28 regulates Igf2-H19 and Dlk1-Gtl2 imprinting by distinct mechanisms during sheep fibroblast proliferation

文献类型： 外文期刊

第一作者： Luo, Jian

作者： Luo, Jian;Zhang, Yiyuan;Guo, Yanhua;Tang, Hong;Wei, Haixia;Liu, Shouren;Wang, Xinhua;Wang, Limin;Zhou, Ping;Wei, Haixia;Liu, Shouren;Wang, Limin

作者机构：

关键词： Trim28;Imprinted gene;Epigenetic;DNA methylation;Proliferation

期刊名称：GENE （ 影响因子：3.688； 五年影响因子：3.329 ）

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收录情况： SCI

摘要： Abstract DNA methylation is an essential epigenetic modification involved in regulating gene expression and maintaining epigenetic information across generations. However, how these marks are recognized and interpreted to activate or repress imprinted genes is not fully understood. Preliminary evidence describes the transcriptional repressor TRIM28 as a key regulator of imprinted gene expression during and after early genome-wide reprogramming. Aberrant expression of imprinted genes maybe one possible cause of incomplete epigenetic reprogramming and low efficiency in somatic cell nuclear transfer. Here, we perform a series of experiments to determine whether knockdown of Trim28 alters imprinted gene expression and DMR methylation in sheep embryonic fibroblast (SEF) cells. siRNA-mediated Trim28 silencing in SEF cells resulted in significantly decreased expression of Gtl2 to 30% and increased expression of Dlk 1 (~1.7-fold). Moreover, knocking down Trim28 induced DNA methylation at the IG-DMR and the Gtl2 promoter was disrupted. Here, we uncover an important role for Trim28 in the maintenance of DNA methylation at IG-DMR during replication-dependent dilution of methylated cytosine during cellular proliferation. Unlike Dlk1-Gtl2 however, knocking down Trim28 does not affect DMR methylation in the Igf2-H19 gene cluster, yet results in increased expression of Igf2 and H19 . Interestingly, Peg3 expression decreased by 60% in Trim28 knockdown cells. PEG3 as a transcriptional repressor to the H19-ICR that interacts with the co-repressor protein TRIM28 through KRAB-A. Trim28 therefore appears to control the Igf2 - H19 imprinted cluster indirectly via PEG3, which is distinct from its classical role in preserving DNA methylation during DNA replication. Our results therefore indicate that Trim28 regulates imprinted gene expression through at least two distinct mechanisms during cells proliferation. Highlights ? We cloned sheep Trim28 and knocked down Trim28 in sheep embryonic fibroblast cells. ? Knocking down Trim28 regulates Dlk1 and Gtl2 expression through inducing DNA methylation at the IG-DMR and the Gtl2 promoter. ? Trim28 control the Igf2 - H19 indirectly via PEG3, which is distinct from its classical role in preserving DNA methylation.

分类号： R394

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